title: PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease.
abstract: A hallmark of Parkinson's disease (PD) is the preferential loss of substantia nigra dopamine neurons. Here, we identify a new parkin interacting substrate, PARIS (ZNF746), whose levels are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human PD brain. PARIS represses the expression of the transcriptional coactivator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons in a PARIS-dependent manner. Moreover, overexpression of PARIS leads to the selective loss of DA neurons in the substantia nigra, and this is reversed by either parkin or PGC-1α coexpression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.
authors.affiliation: NeuroRegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Joo-Ho
authors.initials: JH
authors.lastname: Shin
authors.forename: Han Seok
authors.initials: HS
authors.lastname: Ko
authors.forename: Hochul
authors.initials: H
authors.lastname: Kang
authors.forename: Yunjong
authors.initials: Y
authors.lastname: Lee
authors.forename: Yun-Il
authors.initials: YI
authors.lastname: Lee
authors.forename: Olga
authors.initials: O
authors.lastname: Pletinkova
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troconso
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051265:NF-E2-Related Factor 1 / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D051265:NF-E2-Related Factor 1; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C557561:ZNF746 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine